ABSTRACT
BACKGROUND: Dietary supplementation with zinc has been shown to reduce the duration and severity of diarrhoeal disease caused by Enteropathogenic Escherichia coli, common in infants in developing countries. Initially this therapeutic benefit was attributed to the correction of zinc deficiency in malnourished individuals, but recently evidence has emerged that zinc significantly impacts the pathogens themselves: zinc concentrations achievable by oral supplementation can reduce the expression of key virulence-related genes in EPEC and related organisms. RESULTS: Here, we investigate three possible mechanisms for such zinc-induced changes in expression of EPEC virulence: direct interaction of zinc with regulators of LEE operons; genetic interaction of LEE operons with known regulators of zinc homeostasis; and finally, downregulation of LEE transcription associated with activation of the σ(E) envelope stress response by zinc. We find evidence only for the latter mechanism, including zinc-induced down-regulation of type III secretion in EPEC similar to that caused by ammonium metavanadate, another known inducer of the σ(E) stress response. CONCLUSIONS: We conclude therefore that envelope stress is a major mechanism by which zinc attenuates the virulence of EPEC and related pathogens.
